The
TNF-related apoptosis inducing ligand (TRAIL) has promising anti-
cancer therapeutic activity, although significant percentage of primary
tumors resistant to TRAIL-induced apoptosis remains an obstacle to the extensive use of TRAIL-based mono-
therapies. Natural compound
curcumin could potentially sensitize resistant
cancer cells to TRAIL. We found that the combination of TRAIL with
curcumin can synergistically induces apoptosis in three TRAIL-resistant
breast cancer cell lines. The mechanism behind this synergistic cell death was investigated by examining an effect of
curcumin on the expression and activation of TRAIL-associated cell death
proteins. Immunoblotting, RNA interference, and use of chemical inhibitors of TRAIL-activate signaling revealed differential effects of
curcumin on the expression of Mcl-1 and activities of ERK and Akt.
Curcumin-induced production of
reactive oxygen species did not affect total expression of DR5 but it enhanced mobilization of DR5 to the plasma membrane. In these
breast cancer cells
curcumin also induced downregulation of IAP
proteins. Taken together, our data suggest that a combination of TRAIL and
curcumin is a potentially promising treatment for
breast cancer, although the specific mechanisms involved in this sensitization could differ even among
breast cancer cells of different origins.